r/anhedonia

Galantamine

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• Galantamine has a dual approach:
• It stops an enzyme called acetylcholinesterase from breaking down acetylcholine, letting more of this memory-boosting chemical stay active in the brain.
• It also enhances the activity of nicotinic acetylcholine receptors, which are like switches that help acetylcholine work better, potentially improving communication between brain cells.
• Galantamine may protect brain cells from damage by acting as an antioxidant and reducing inflammation.
• Tertiary alkaloid drug.
• Reversible, competitive inhibitor of acetylcholinesterase (AChE). This enzyme typically hydrolyzes acetylcholine (ACh), a neurotransmitter critical for memory, thinking, and reasoning, into choline and acetate. By inhibiting AChE, Galantamine increases the concentration of ACh in the synaptic cleft, thereby enhancing cholinergic neurotransmission. This action is particularly relevant in AD, where cholinergic deficits are a hallmark.
• Research indicates Galantamine is 50-fold more selective for AChE over butyrylcholinesterase (BuChE), with an IC50 for AChE of 0.35 μM and for BuChE of 18.6 μM.
• It has a bioavailability of 80–100%, a protein binding of 18%, and an elimination half-life of 7 hours, with peak AChE inhibition occurring approximately 1 hour after an 8 mg oral dose in healthy volunteers (source).
• Acts as a positive allosteric modulator of nicotinic acetylcholine receptors (nAChRs), particularly the α7 and α4β2 subtypes. This means it binds to allosteric sites on these receptors, triggering a conformational change that enhances their response to ACh. At concentrations of 0.1–1 μM, it potentiates agonist responses, while at higher concentrations (>10 μM), it may inhibit activity ().
• Exhibits significant neuroprotective properties. It acts as an antioxidant, scavenging reactive oxygen species (ROS) and protecting neurons from oxidative damage (source).
• Prevents the activation of microglia and astrocytes, key players in neuroinflammation, and counters the expression of inflammatory markers such as NF-κB, p65, TNF-α, IL-1β, and IL-6 in the hippocampus (source).
• Increases the levels of glutamate, serotonin, norepinephrine, dopamine, and GABA.
• Stimulates vascular endothelial growth factor (VEGF) through nicotine receptors, increasing phosphorylation of Akt and CREB, and reducing the expression of FoXO1, MuRF-1, and atrogin-1. This enhances the release of acetylcholine, ATP, and brain-derived neurotrophic factor (BDNF), potentially supporting muscle function.
• It stimulates proliferation in the hippocampus subgranular zone via M1 muscarinic receptors and supports cell survival through α7 nAChRs, involving insulin-like growth factor 2.
• Clinical studies have shown Galantamine reduces cocaine use frequency at 8 mg/day and improves sustained attention and response inhibition in cigarette smokers, as well as decreasing alcohol consumption in detoxified individuals.
• The dual mechanism of AChE inhibition and nAChR modulation is central to Galantamine's efficacy in AD. Clinical trials have demonstrated improvements in cognitive function, with doses ranging from 8–32 mg/day showing benefits over 3–6 months, sustained at 24 mg/day for 12 months.
• Galantamine is well-absorbed, with linear pharmacokinetics and rapid, complete absorption. About 75% is metabolized in the liver via CYP2D6 and CYP3A4, with key pathways including O-demethylation, N-demethylation, epimerization, and glucuronidation. Within 24 hours, approximately 20% is excreted unchanged in urine.

• Summary Table: Key Pharmacological Actions

• • Action	Description
    AChE Inhibition	Reversible, competitive, selective; increases ACh levels, IC50 for AChE: 0.35 μM.
    nAChR Modulation	Positive allosteric modulator of α7, α4β2 subtypes; enhances receptor sensitivity at 0.1–1 μM.
    Neuroprotection	Antioxidant, inhibits Aβ aggregation, promotes neurogenesis via M1, α7 receptors.
    Anti-Inflammatory Activity	Prevents microglia/astrocyte activation, reduces NF-κB, TNF-α, IL-1β, IL-6.
    Neurotransmitter Modulation	Increases glutamate, serotonin, norepinephrine, dopamine, GABA release.
    Neuromuscular Effects	Stimulates VEGF, enhances ACh, ATP, BDNF release, affects Akt, CREB pathways.
    Neural Proliferation	Stimulates hippocampal progenitor cells via M1, α7 receptors, involves IGF-2.
    SUDs Treatment	Reduces cocaine use, improves attention in smokers, decreases alcohol consumption.